17 - (unsaturated hydrocarbon - substituted) 11,13beta - dialkylgon -4 - ene - 3,17beta-diols and esters thereof



United States Patent 3,465,010 17 (UNSATURATED HYDROCARBON SUBSTI- TUTED) 11,135 DIALKYLGON 4 ENE 3,175- DIOLS AND ESTERS THEREOF John S. Baran, Morton Grove, Ill., assignor to G. D. Searle & Co., Chicago, 111., a corporation of Delaware No Drawing. Filed Nov. 22, 1966, Ser. No. 596,090 Int. Cl. C07c 169/08, 169/12; A61k 17/00 U.S. Cl. 260-3975 8 Claims ABSTRACT OF THE DISCLOSURE 17-(unsaturated hydrocarbon-substituted) 11,-l3/3-dialkylgon-4-ene-3,17,8-diols manufactured by reaction of the corresponding 3-keto starting materials with a suitable reducing agent and the esters of those diols display useful pharmacological properties, e.g., progestational and deciduogenic.

The present invention is concerned with novel organic chemical compounds of the steroid family in which there is invariably present an ll-alkyl substituent. More particularly, these compounds are 17-(unsaturated hydrocarbonsubstituted) 1l,13fi-dialkylgon-4-ene-3,l7fl-diols and the corresponding esters which are represented by the following structural formula In that structural representation, R and R are lower alkyl radicals, X denotes a lower unsaturated aliphatic hydrocarbon radical, Y and Z can be either hydrogen or a lower alkanoyl radical and the wavy line indicates the alternative or or ,8 stereochemical configuration.

The lower alkyl radicals symbolized by R and R are exemplified by methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and the branched-chain radicals isomeric therewith.

Typical of the lower alkanoyl radicals signified by the Y and Z terms are formyl, acetyl, propionyl, butyryl, valeryl, caproyl, heptanoyl and the branched-chain isomers thereof.

The lower unsaturated aliphatic hydrocarbon radicals denoted by X are typified by ethynyl, vinyl, propynyl, allyl, butynyl, propargyl, methallyl, etc.

Manufacture of the compounds of the present invention is conveniently achieved by processes which utilize as starting materials compounds of the following structural formula 3,465,010 Patented Sept. 2, 1969 ICC potassium borohydride, lithium tri-(tertiary-butoxy) aluminum hydride or diisobutyl aluminum hydride, conversion of the 3-keto to a S-hydroxy function occurs. That process is carried out typically at room temperature, preferably in the presence of a suitable inert organic solvent. As a specific example, the reaction of 170t-6thYI1Yl-17j3- hydroxy-l1fi-methylestr-4-en-3-one with lithium tri-(tertiary-butoxy) aluminum hydride in tetrahydrofuran at room temperature results in l7a-ethynyl-l lB-methylestr-4- ene-3fl-l7B-diol.

Esterification of the instant 3-hydroxy substances by reaction with a lower alkanoic acid anhydride or halide at room temperature, preferably in the presence of a suitable acid acceptor, in the case of the instant 3,17-diols results in the corresponding 3-mono-(lower alkanoates) and, in the case of the instant 17-mono-(lower alkanoates), afords the instant 3,17-bis-(lower alkanoates). Specific examples of that process are the reaction of l7a-ethynyl- 1lB-methylestr-4-ene-3B,17B-diol or 17a ethynyl 11 8- methylestr-4-ene-318,17,6-diol-17-acetate with acetic anhydride and pyridine at room temperature to afford 17aethynyl 115-methylestr-4-ene-3B,17B-diol 3-acetate and 17ot-ethynyl-1lfi-methylestr-4-ene-3fi,17B-diol 3,17 diacetate, respectively.

The instant 3,17-bis-(lower alkanoates) are produced also by acylation of the corresponding 3,17-diols at elevated temperature. The aforementioned 17a-ethynyl-11pmethylestr-4-ene-3fi,17,8-diol is thus heated at 100 for about 18 hours with acetic anhydride and pyridine to aford 17a-ethynyl-11,8-methy1estr-4-ene-3fl,l7fl-diol 3,17-diacetate.

The instant compounds wherein the 13B-alkyl group contains more than one carbon atom are obtained as dl mixtures. Resolution of these dl compounds to afford the individual d and l enantiomorphs is conveniently effected by esterification of the hydroxy group with a dibasic anhydride such as succinic or phthalic anhydride to afford the corresponding acid ester, which is resolved by means of an optically active amine such as brucine, morphine, quinine, quinidine, strychnine, etc.

The compounds of the present invention are useful in consequence of their valuable pharmacological properties. In particular, they are hormonal agents as is evidenced by their potent progestational and deciduogenic activity.

The invention will appear more fully from the examples which follow. These examples are given by way of illustration only and are not to be construed as limiting the invention either in spirit or in scope as many modifications both in materials and methods will be apparent from this disclosure to those skilled in the art. In these examples temperatures are given in degrees centigrade C.) and quantities of materials in parts by weight unless otherwise noted.

Example 1 To a solution of one part of 17a-ethynyl-17p-hydroxyl1/3-methylestr-4-en-3-one in 27 parts of tetrahydrofuran is added 4 parts of lithium tri(tertiary-butoxy) aluminum hydride, and the resulting reaction mixture is stirred at room temperature for about 2 hours. The mixture is then poured with stirring into an aqueous mixture containing 40 parts of water, 20 parts of ice and 10.5 parts of acetic acid. Extraction with chloroform affords an organic solution, which is washed successively with aqueous sodium chloride and aqueous sodium bicarbonate, then dried over anhydrous magnesium sulfate and distilled to dryness under reduced pressure. The resulting crude product is purified by recrystallization from etherhexane to yield 17a-ethynyl-11B-methylestr-4-ene- 35,17,8-diol, melting at about 175480". This compound exhibits infrared absorption maxima, in a potassium bromide disc, at about 2.82, 2.90, 3.06, 7.21, 9.34, 9.67,

H. 3 an Example 2 A mixture containing one part of 17u-ethynyl-1l5- methylestr-4-ene-35,l7/8-diol, parts of acetic anhydride and parts of pyridine is heated on the steam bath for about 18 hours, then is cooled and concentrated to dryness under reduced pressure. The resulting solid residue is extracted with ether, and the ether solution is Washed several times with saturated aqueous sodium chloride, then dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. Purification by recrystallization from methanol affords pure 17aethynyl 11 8 methylestr 4 ene 3 3,176 diol 3,17- diacetate, melting at about 148. This compound is represented by the following structural formula OCOCHa Example 3 O CHsiiO- By substituting an equivalent quantity of propionic anhydride and otherwise proceeding according to the processes described in Example 2, there is obtained 170tethynyl 11,8 methylestr 4 ene 35,1718 diol 3,17- dipropionate.

Example 4 When an equivalent quantity of dl-17ot-ethynyl-13 8- ethyl-17fl-hydroxy-1lfi-methylgon-4-en 3 one is substituted in the procedure of Example 1, there is produced dl 17cc ethynyl 13B ethyl 11p? methylgon 4 ene- 318,17fi-diol.

Example 5 By substituting an equivalent quantity of dl-17u-ethynyl 135 ethyl 11B methylgon 4 ene 35,17,8-diol and otherwise proceeding according to the processes described in Example 2, there is obtained dl-l7a-ethynyl- 13,8 ethyl 11B methylgon 4 ene 35,175 diol, 3,17-diacetate.

Example 6 The reduction of an equivalent quantity of llfl-ethyl- 17a-ethyny1-17,8-hydroxyestr-4-en-3-one by the procedure described in Example 1 results in 1lfl-ethyl-17ot-ethynyl estr-4-ene-3{3,17,8-diol.

Example 7 4 Example 9 The reaction of an equivalent quantity of llfl-methyl- 17ot-vinylestr-4-ene-3fi,17p-diol with acetic anhydride according to the procedure described in Example 2 results in 1lfi-methyl-17ot-vinylestr-4-ene-3fi,17,8-diol 3,17-diacetate.

Example 10 With an equivalent quantity of 17,8-hydroxy-l1B- methyl-17ot-propynylestr-4-en-3-one is substituted in the procedure of Example 1, there is produced llfi-methyl- 17u-propynylester-4-ene-3 B,17fi-diol.

Example 11 The reaction of an equivalent quantity of llfi-methyl- 17a-propynylestr-4-ene-3B,17,8-diol with acetic anhydride by the procedure described in Example 2 results in 116- methyl 17a propynylestr 4 ene 35,175 diol 3,17- diacetate.

Example 12 By substituting an equivalent quantity of 17fl-hydroxy- 11B methyl 17cc propenylestr 4 en 3 one and otherwise proceeding according to the processes described in Example 1, there is produced 11,6-methyl-17u-propenylestr-4-ene-3fl,17fi-diol.

Example 13 The substitution of an equivalent quantity of 11/i methyl 17a propenylestr-4-ene-3fl,17,8 diol in the procedure of Example 2 results in 1lB-methyl-17ot-propenylestr-4-ene-3fi,17,8-diol 3,17-diacetate.

Example 14 To a solution containing 70 parts of liquid ammonia, 45 parts of tetrahydrofuran and 5.6 parts of tertiary-butyl alcohol is added a solution of 1 part of 3-methoxy-11otmethylestra-1,3,5(10)-trien-17-one in 18 parts of tetrahydrofuran, and the resulting reaction mixture is stirred while 0.5 part of sodium is added over a period of about 40 minutes. At the end of that time, the blue color is destroyed by the addition of approximately 8 parts of methanol, and the solution is evaporated to dryness under reduced pressure. Trituration of the residual solid material with ice water affords 11ot-methylestra-2,5(10)-diene 3,17/3-diol 3-methyl ether.

A solution containing 8 parts of l1ot-methylestra-2,5 (10)-diene-3,17{3-diol 3-methyl ether, 870 parts of toluene, 20 parts of aluminum isopropoxide and 47.5 parts of cyclohexanone is heated at the reflux temperature for about one hour, then cooled, following which time 500 parts by volume of saturated aqueous sodium potassium tartrate is added. The volatile organic material is removed by steam distillation and the resulting aqueous residue is cooled and extracted with ether. Drying of the ether extract over anhydrous magnesium sulfate followed by concentration of the solution to dryness affords a residue, which is treated with hexane to afford 3-methoxy-1lot-methylestra- 2,5(10)-dien-17-one.

A mixture of 1 part of 3-methoxy-11ot-methylestra-2,5 (l0)-dien-17-one, 25 parts of the 30% lithium acetylide- 70% ethylene diamine complex and 450 parts of tetrahydrofuran is stirred in a nitrogen atmosphere at about 0 for approximately 2 /2 hours, then is diluted with approximately 500 parts of water. The resulting mixture is partially concentrated under reduced pressure, then is extracted with ether. The ether extract is washed With dilute aqueous sodium chloride, then is dried over anhydrous magnesium sulfate and concentrated to dryness under reduced pressure. The residue which contains 17ot-ethynyl- 1lot-methylestra-2,5(l0)-dien-3,l7/3-diol 3-methyl ether is dissolved in parts of methanol, and a solution of 20 parts of 4 N hydrochloric acid in 20 parts of water is added. That solution is heated on the steam bath for about 10 minutes, then is cooled and neutralized by the addition of aqueous sodium bicarbonate. Concentration of that solution to dryness affords the crude product, which is treated with decolorizing carbon to yield l7a-ethynyl-l7fi hydroxy-l 1a-methylestr-4-en-3-one.

The substitution of an equivalent quantity of 170:- ethynyl-17 8-hydroxy-1la-methylestr4 en 3 one in the procedure described in Example 1 results in l7a-ethynyll la-methylestr-4-ene-3 B, l7fl-diol.

Example When an equivalent quantity of 17oc-fithYI1Yl-1loc-1Tlethylestr-4-ene-3fl,l7fl-diol is substituted in the procedure of Example 2, there is produced 17ot-ethynyl-1la-methylestr- 4-ene-3 B, 17 ,B-diol 3,17-diacetate.

Example 16 When an equivalent quantity of 11a-methyl-17a-vinylestr-4-ene-3 8,17B-diol is acylated by the procedure described in Example 2, there is obtained 11u-methyl-l7avinylestr-4-ene-3fl, l7fl-diol 3 l'7-diacetate.

What is claimed is:

1. A compound of the formula wherein X is a lower aliphatic unsaturated hydrocarbon radical, Y and Z are selected from the group consisting of hydrogen and a lower alkanoyl radical and R and R are lower alkyl radicals.

2. As in claim 1, a compound of the formula wherein X is a lower aliphatic unsaturated hydrocarbon radical, Y and Z are selected from the group consisting of hydrogen and a lower alkanoyl radical and R is a lower alkyl radical.

3. As in claim 1, a compound of the formula wherein X is a lower aliphatic unsaturated hydrocarbon radical and Y and Z are selected from the group consisting of hydrogen and a lower alkanoyl radical.

4. As in claim 1, a compound of the formula wherein X is a lower aliphatic unsaturated hydrocarbon radical.

5. As in claim 1, a compound of the formula Clixil 6. As in claim 1, a compound of the formula --(lower alkynyl) 0 Ha- 1 wherein Y and Z are lower alkanoyl radicals.

7. As in claim 1, the compound which is 17a-ethynyl- 1 1 p-methylestr-4-ene-3 B, 17 fi-diol.

8. As in claim 1, the compound which is 17u-ethyny1- 1lfi-methylestr-4-ene-3 8,l7B-diol 3,17-diacetate.

References Cited UNITED STATES PATENTS 3,346,602 10/1967 Baran 260--397.45 2,843,609 7/ 1958 Colton. 3,176,013 3/1965 Klimstra.

LEWIS GO'ITS, Primary Examiner.

E. G. LOVE, Assistant Examiner US. Cl. X.R. 260-397.45, 999 

